Neuronal ABCA7 loss of function and Alzheimer’s disease

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PROJECT SUMMARY/ABSTRACT MAYO CLINIC JACKSONVILLE Current genetic studies indicate that susceptibility loci in late-onset Alzheimer’s disease (AD) are correlated with lipid metabolism. While ATP-binding cassette transporter A7 (ABCA7) gene variants are strongly associated with AD risk, the premature termination codon (PTC) mutations in ABCA7 significantly increases the risk for both early-onset and late-onset AD. ABCA7 belongs to the ABC transporter family regulating distribution of lipids and other lipid-related molecules across cellular membranes. Thus, exploring functions of ABCA7 in lipid metabolism should provide us important clues to determine the central pathogenic pathway for AD. While ABCA7 expression is the highest in neurons among brain cell types, our preliminary study showed that ABCA7 deficiency alters the compositions of mitochondria-related lipids and impairs mitochondria function accompanied with synaptic dysregulation in the cortical organoids and neurons derived from human induced pluripotent stem cells (iPSCs). In addition, RNA-sequencing analysis also found that pathways related to fatty acid β-oxidation in mitochondria and cellular membrane homeostasis are predominantly affected by ABCA7 deficiency in mouse brains. As lipids substantially contribute to the regulation of neuronal functions, we hypothesize that ABCA7 loss of function alters the lipid metabolism among cellular organelles, and disturbs mitochondria functions in neurons, resulting in neurodegeneration and synaptic dysfunction during aging and AD. Therefore, this proposal uniquely aims to dissect how ABCA7 deficiency impacts lipid metabolism in neurons and contributes to AD-related phenotypes including mitochondria dysregulation and synaptic dysfunction. In Aim 1, we will examine how ABCA7 deficiency influences lipid metabolism, mitochondria function, and AD-related phenotypes using iPSC-derived neurons and cortical organoids. In Aim 2, we will dissect roles of neuronal ABCA7 in AD-related phenotypes using neuron specific Abca7 knockout mouse models with or without amyloid pathology, accompanied with single cell-RNA sequencing. In Aim 3, we will explore impacts of ABCA7 deficiency on synapses, including mitochondria functions and lipid profiles, by isolating synaptosomes from conventional Abca7 knockout mice as well as neuron specific Abca7 knockout mice with or without amyloid pathology. Collectively, these studies should provide us new insights for the molecular mechanisms in which ABCA7 floss of function causes the pathogenic processes of AD by disturbing neuronal lipid homeostasis.